1-Aryl-n-dialkylaminoalkyl-3,4-dihydro-2(1H)-isoquinolinecarboxamides and related compounds

ABSTRACT

1-Aryl-N-dialkylaminoalkyl-3,4-dihydro-2(1H)isoquinolinecarboxamides and related N-substituted amides having anti-arrhythmic, anti-bacterial, anti-fungal, anti-algal and anthelmintic activity are described herein. The subject compounds can be prepared by reacting the appropriate 3,4-dihydro-2(1H)isoquinolinecarbonyl chloride with a dialkylaminoalkylamine or similar compound, or by reacting an N-(chloroalkyl)-3,4-dihydro2(1H)-isoquinolinecarboxamide with the appropriate dialkylamine or similar compound.

United States Patent 91 Yonan l-ARYbN-DlALKYLAWNOALKYL-3,4-

D1HYDRO-2( 1H)- ISOQUINOLINECARBOXAMIDES AND RELATED COMPOUNDS [75] inventor: Peter K. YOIIIII, Morton Grove. ill.

[73] Aulgnee: G. D. Searle 8L Co.. Chicago. Ill. 221 Fllod: .ltlly 2:. 1m

[21] Appl. No.: 381,505

[52 us Cl. ..260/28/ R; 260 2415 GP; 260/268 BQ; 260/283 SY; 260/283 R;

260/289 R; 260/559 D; 260/286 R:

260/570.5 R; 260/611 R; 424/25 P;

[51] .Int. Cl. C07D 217/06 [58] Field of Search 260/287 [56] References Cited UNITED STATES PATENTS 3.483.206. 12/1959 Werner 260/287 3.524.858 8/1970 Karninsky et al. 260/287 51 Sept. 16, 1975 3.634.429 1/1972 Leimgrubcr et al. 260/287 3.666.763 5/1972 Grctlhe 260/289 R OTHER PUBLICATiONS Perron et al.. J. Med. Chem. Jan. 1966. Vol. 9. p. 141.

Primary Examiner-Donald 0. Dau: Ass/nan: Examiner-David B. Wheeler Attorney. Agent. or Firm-John J. Kotano 12 Clahm, No Drawings The present invention relates to a group of 5 3 ,4-dihydro-2( l H )-isoquinolinecarboxamides. More particularly. the present invention relates to a group of compounds having the oeneral formula X ll -c-lf-Alk-IR'R" I R an I) wherein X and X are each selected from the group consisting of hydrogen, lower alkoxy, hydroxy. benzyloxy and lower alltyl, or X and X together represent a single methylenedioxy or ethylenedioxy group; Y and Y are each selected from the group consisting of hydrogen. halogen and lower alkoxy; n is selected from the group consisting of 0 and l; R is selected from the group consisting of hydrogen and lower alltyl; All: is lower alkylene separating the nitrogen atoms attached thereto by at least 2 carbon atoms; and NR'R" is selected from the group consisting of di(lower alkyl- )amino, N-cycloalltyl(lower alkylamino), l-

pyrrolidinyl. hexamethyleneimino, morpholino. piperi- 7 dipropylamino, diisopropyl=amino and the like. The

lower aikylene groups referred to above contain 2 to 6 carbon atoms and can be exemplified by groups such as ethylene. propylene. trimethylene and 1,4-

. pentylcne. The halogen atoms include fluorine, chlorine. bromine and iodine. The cycloalkyl groups contain to 7 carbon atoms and include cyclopentyl, cyclohexyl and cycloheptyl.

Equivalent to the compounds of formula (I) for the purposes of this invention are the pharmaceutically acceptable acid addition and quaternary ammonium salts 'thereof. Such acid addition salts can be derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric. hydrobromic, hydriodic. sulefamic. citric. lactic. maleic. malic. succinic, tartaric. cinnarnic. acetic. benzoic. gluconic. ascorbic and re- .lated acids. Similarly, the quaternary ammonium salts can be derived from a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. Among such esters are methyl chloride and bromide, ethyl chloride. propyl chloride. butyl chloride, isobutyl chloride. benzyl chloride and bromide. phenethyl bromide. naphthylmethyl chloride, di-methyl sulfate, methyl benzenesulfonate. ethyl toluene-sulfonate, ethylene chlorohydrin. propylene chlorohydrin. allyl bromide.

methallyl bromide and crotyl bromide.

The compounds of this invention are useful because of their pharmacological properties. in particular, they possess activity as anti-arrhythmic agents. Thus. they bring about a return to normal heat rhythm in animals in which the heart rhythm has become irregular.

The anti-arrhythmic utility of the instant compounds is evident from the results of a standardized test for their capacity to slow the ventricular tachycardia induced by aconitine in the isolated rabbit heart. The procedure is essentially that described by Lucchesi [1. Pharrnacol. Exp. Therap.. 137. 291 0962)], modified in certain. particulars as follows: Hearts are obtained from adult albino rabbits of either sex and perfused in apparatus modeled after that devised by Anderson and Craver [.l. Pharrnacol. Exp. Therap.. 93.135 (i948 )1. The composition of the perfusion solution is the same as Lucchesi's, but the volume is increased to 200 ml. and the temperature lowered to 28C. Aconitine (ordinarily as the nitrate) is administered as soon as the heart beat is regular and the EKG pattern normal, the dose being so selected as to at least double the rate. Typically, 0.05 ml. of 0.l% aconitine nitrate in physiological saline is injected. EKG's are recorded at 5 minute intervals after onset of ventricular tachycardia until two successive readings show stabilization of the rate. Perfusate collected during this time is discarded and replaced with fresh solution q.s. 200 ml. Promptly following stabilization. 2 mg. of compound dissolved or suspended in l ml. of physiological saline is mixed with the perfusion solution. Ten minutes later a like amount is introduced, followed after a further ten minutes by double the first amount. 'Final concentration of com- 3,4-dihydro-2( iii )-isoquinolinecarboxamide; 6,7- dimethoxy-l-phenyl'N-(2-pipe|idinoethyl)-3.4- dlhydro-2(l l-l)-isoquinolinecarboxamide; N-(Z-diisopropylaminoethyl)l -phenyl-3,4dihydro-2(l H)- isoquinolinecarboxamide; N-{Z-[N-cyclohexyl(methylamino)]ethyl} 6,7-dimethoxy-l-phenyl- 3,4-dihydro-2(lH)-isoquinolinecarboxamide; and 7-benzyloxy-N-{2-[N-cyclohexy(methylamino)] ethyl}-6-methoxyl -phenyl-3 ,4-dihydro-2(l H)- isoquinolinecarboxamide.

The compounds of the present invention also possess anti-biotic activity against a variety of micro=organisms. Thus, they inhibit the growth of bacteria such as Bacillus subtills and Erwlnla sp., fungi such as Verticilllum aIbo-atrum and algae such asChlorella vulgarir. in

addition, they possess anthelmintic activity. By virtue of their anti-biotic activity. these compounds can be combined with various known excipients and adjuvants in the form of dusts, solutions, suspensions, ointments and sprays to provide compositions useful for disinfecting purposes.

The compounds of the present invention can be conveniently prepared by contacting a compound of the formula wherein X, X, Y, Y', n, R, All: and NR'R" are defined as before. Depending on the nature of the reactants, it is possible to carry-out this reaction inthe presence or absence of, a solvent. The use of a solventis, however,

generallypreferred. An especially desirable solvent is chloroform, while other; possible solvents would include aromatic hydrocarbons such as benzene and tolu- 35 ene, halogenated hydrocarbons such as methylene chloride andicarbon tetra==chloride, ltetones such as acetone and 2-butanone and ethers such as ethyl ether, tetrahydrofuran and dioxane. Time and temperature are not critical factors for the conduct of this reaction, typical temperatures varying from room temperature to reflux and typical times being in sewage of 30 minutes to several days. I

An alternate route to the subject compounds involves contacting a compound of the formula with an appropriate secondary amine of the formula H- -NR'R" 6 wherein X, X, Y, Y, n, All: and NR'R" are defined as before. This reaction is conducted in a suitable'solvent, preferably a ketone (c.g., Z-butanone or ace-' tone). Other possible solvents include aromatic hydro carbons (e.g., benzene and toluene), high boiling cthers (e.g., dioxane), lower allkanols (e.g., methanol and ethanol), dimethylformamide and dimethylsulfoxide. Time and temperature are not critical.-Reaction temperature can vary from room temperature to approximately l00C., with a temperature range of room temperature to 6070C. being typical. Time varies from a few hours to several days, depending on the particular temperature employed.

An alternative process for the preparation of the subject compounds wherein R is a lower allsyl group proceeds by contacting a compound of formula I) wherein R is hydrogen with a lower alltyl halide in the presence of sodium hydride or sodamide. The reaction is conducted in a solvent which is unreactive toward the sodium hydride or sodamide employed, the solvent of choice being dimethyl=sulfoxidel Other possible solvents include ethcrs such as tetrahydrofuran and dioxane. When sodamide is used, it; is also possible to employ an aromatic solvent, e.g., benzene or toluene. Time and temperature are not critical. The reaction can be conducted at a temperature ranging from room temperature to lO0C., with a temperature range of room temperature 60-70C. being preferred. Reaction time usually varies from 3 to 24' hours.

The compounds of formula (l) wherein X and/or X are/is hydroxy can be prepared from the corresponding compounds of formula (I) wherein X and/or X are/is benzyloxy. Debenzylation is conveniently effected by catalytic hydrogenolysis. Suitable catalysts include platinum, Raney nickel, copper-chromium oxide and palladium (optionally on a support), a particularly preferred catalyst being palladium-on-carbon. The hydrogenation is conveniently conducted in a solvent, the choice of solvent depending upon the particular starting material employed. Generally speaking, a wide variety of solvents, such as lower alkanols (e.g., methanol, ethanol and 2-propanol), ethers (e.g., tetrahydrofuran), water and acetic acid, could be used. The reaction is generally conducted at a temperature ranging from room temperature to 100C, with a temperature range of room temperature to 50-60C. being typical.

The novel starting materials of formula (ll) above can be readily prepared by contacting a compound of the formula wherein X, X', Y, Y and n are: as hereinbefore defined with phosgene.

-)Certain of the starting materials'of formula (ill) above canbe prepared from the corresponding compounds of formula (IV) by treatment with a chloroalk- .ylisocyanate of the formula wherein Alk is defined as before.

The invention will appear more fully from the examples which follow. These examples are given by way of illustration only and are not to be construed as limiting the invention either in spirit or in scope as many modifications both in materials and methods will be apparent to those skilled in the art. In these examples, temperatures are given in degrees centigrade and quantities of materials are expressed in parts by weight unless otherwise specified. The relationship between parts by weight and parts by volume is the same as that existing between grams and milliliters.

EXAMPLE 1 A mixture of 50 parts of 3-benzyloxy-4- methoxybenzaldehyde, 25 parts of nitromethane, 2.1 parts of glacial acetic acid and 2.2 parts of nbutylamine in 39.5 parts of ethanol is heated until dissolved. The resulting solution is allowed to stand overnight. The crystals which form are separated by filtration and washed with ethanol. There is thus obtained 3-benzyloxy-4-methoxy-Bnitrostyrene, melting at about l26-l28C.

Substitution of a like quantity of 4-benzyloxy- 3-methoxybenzaldehyde for the 3-ben2yloxy-4 methoxybenzaldehyde used above and substantial repetition of the foregoing procedure gives 4-benzyloxy-3- methoxy-B-nitrostyrene. melting at about ll8-l 21C.

Substitution of an equivalent quantity of 3.4-methylenedioxybenzaldehyde or 3,4-ethylenedioxybenzaldehyde for the 3-benzyloxy-4- methoxybenzaldehyde used above and substantial repetition of the procedure detailed in the first paragraph .of this example affords 3,4-methylenedioxy-B- nitrostyrene or -e thylenedioxy-B-ethylenedioxy-B- nitrostyrene. respectively.

EXAMPLE 2 To a suspension of parts of lithium aluminum hydride in 444 parts of tetrahydrofuran and 177 parts of ethyl ether is added portionwise, over a l hour period, a warm solution of 56 parts of 3-benzyloxy-4-methoxy- B-nitrostyrene in 267'parts of tetrahydrofuran. The re action mixture is refluxed for an additional 2 hours. then is cooled in ice and decomposed by adding 40 parts of water in 71 parts of tetrahydrofuran, followed by 40 parts by volume of a 25% by weight aqueous sojdium hydroxide solution, followed by 40 parts of water. The salts are removed byjfiltration and the filtrate is dried over anhydrous calcium sulfate and stripped of solvent under reduced pressure to afford, as an oil, 3-

3.4-methylenedioxyphenethylamine or 3.4-ethylenedioxyphenethyl=amine. respectively.

EXAMPLE 3 A solution of 45 parts of benzoyl chloride in 149 parts of chloroform is added portionwise over a 30 minute period to a solution of 78 parts of .3-benzyloxy- 4-methoxyphenethylamine in 72 parts of triethylamine and 596 parts of chloroform. The mixture is stirred at room temperature for an additional minutes. it is then washed twice with water and once with dilute aqueous sodium bicarbonate solution. dried over anhydrous calcium sulfate and stripped to a low volume under reduced pressure. Addition of n-hexane results in crystallization of N-(Zi-benzyloxy- 4-methoxyphenethyl)bcnzamide. That product melts at about l36-l38C.

EXAMPLE 4 A solution of64 parts of N-(3-benzyloxy-4- methoxyphenethyl)benzamide and 192 parts of phosphorus oxychloride in 348 parts of toluene is refluxed for 3 and hours. The solution is stripped in vacuo -until a precipitate forms. Ethyl ether is added and the mixture is filtered. The solid residue. which is 6- benzyloxy- 7-methoxyl -phenyl-3 ,4-dihydroisoquinoline hydrochloride, is dissolved in water. Dilute aqueous sodium hydroxide solution is added and the mixture is extracted with methylene chloride. The methylene chloride extract is dried over anhydrous calcium sulfate and concentrated to a low volume and n-hexane is then added. The crystals which form are separated by filtration. There is thus obtained 6-benzyloxy- 7-methoxyi phenyl-3.4-dihydroisoquinoline, melting at about l44-'-l45C.

The above procedure is repeated using a like quantity of N-(4-benzyloxy-3-metlhoxyphenethyl)benzamide in place of the N-(3-benzyloxy-4-methoxyphenethyl)ben- 'zamide. in this manner. there is obtained 7-benzyloxy- 6-methoxy-l-phenyl-3,4-dihydroisoquinoline, melting at about l34-i37C.

Substitution of an equivalent quantity of N-(3,4- methylenedioxyphenethyl)benzamide or N-(3,4- ethylenedioxyphenthyl)benzamide for the substituted benzamide called for in the first paragraph of this example and substantial repetition of the procedure there detailed affords 6,7-methylenedloxyl -phenyl-3 ,4'dihydrolsoquinoline or 6.7 -ethylenedioxy-l-phenyl-3,4-dihydroisoquinoline, respectively.

EXAMPLE 5 tered. The solid thus obtain is 6,7-dimethoxy-l-phenyl- A suspension of 38 parts of 6-bcnzyloxy-7-methoxyy -Z(lF )osoqutn ztlmecarbonyl ChlOlldc, l-phenyl-3,4-dihydroisoquinoline in 435 parts of etha- P nol is heated to approximately 55C. 32 Parts of sodium subst'muon of cquwalcm of thc borohydride is added portionwise over a minute pertctrahydmisoquinofines indicated bdow for iod, while maintaining the reaction temperature at F ll -C. The mixture is stirred for an additional 3 above and submm'al f foregomg hours at approximately 50C. and a precipitate forms. prpccdure affords h follow! products The reaction mixture is then poured into water and the W of Y- YP "y )1 2.3.4-

precipitate is separated by filtration. affording 6- mmhydmiwquimlim afford! r ybenzyloxy-7-methoxyl -phenyl-l ,2.3.4- y y )-3. y tetrahydrolsoqulnollne. melting at about ll8-li9C. lwqulnollnssarbonyl l rid m s at about Substitution of a like quantity ofv7-benzyloxyi d-methoxy-l-phenyl-3,4-dihydroisoquinoline for the Use 6t7-dimethoxy-l-(fifidimethoxyphenylb tS-benzyloxyp x p r l,2,3,4-tetrahydroisoquinoline affords 6.7-dimethoxy- 7-methoxy-l-phenyl-3,4-dihydroisoquinolinei used g i yp n' Y abo ve and substantial repetition of the foregoing procelsqumolmcafbonyl chloride as f dure gives 7- enzyl0Xy-6-methoxy-l-phenyi-l3,3,4. Use of l-phenyl-l,2.3,4-tetrahydroisoqumoline aftetrahydroisoquinoine, meltingat about l23- i25C. f9"? r b s f1 isoquinoinecar ony c on e,asan or.- 6 i i r afl gm? l f of Use of 6-benzyloxy-7-methoxy-l-phenyl-l3,3,4- me yene '9"!- 'l f 'f' 't tetrahydroisoquinoline affords 6-benzyloxy-7- or 6,7-ethylenedioxyl-phenyl-Zi;4-dihydroisoqu|nolme meth'oxyb H for the SUbStltUiEd3,4-qlhydfOlS0i-1Ull10llnE called form 25 pheny l 3,4 dihydm 2( 1 H) isdquiinolinecarbonyl ch]o the first paragraph ofthis example and substantralreperidfasawaxyisofi of mgi dl fi r affqtds [I Use of 7-benzyloxy-6-methoxyl-phenyl-1,2,15,4- '7'methylenedloxyl'i i t et rahydroisoquinoline, affords 7-benzyloxy-6- r nethoxy-l phenyl-l,2,3,4-tetrahydroisoquinoline or6J-ethylener -P yl-t.2,3.4-tet hyd q respec phenyl 3;4-dihydro 2(il-l)-isoquinolinecarbonyl chlotively' ride, as a waxy solid.

r I Use 3A of l-benzyl-oJ-dimethoxy-l.2,3,4- EXAMPLE 6 ttetrahydroisoquinolinev affords l-benzyl-6,7-

' i r if dimethoxy 3.4-dihydro-2(lH)-isoquinolinecarbonyl 50 Parts of p-fluorobenzaldehy de and parts of 3s 8 d=.;ne:ti(ngalt1lab0urtl lZfi-lgfgl h .1 2 3 4 3.4- dimethoxyphenethylamine are combined and 5 9? my 7 9 P Y v heated overa a'steam ba'th in anitrogen atomsphere for Y l qPlP affords *(4' fP Uy minutesJTI ien SOO" parts by volume of '20% by gitms i-d h -2(lH) -1wq bny weight hydrochloric acid is added'and heating is con- -W9 l v r j v tinued-for an additional 3; hours; The reaction mixture" Use of v7'q Tfl Q9mP FDyU- 3.3. is cooled,madealkalinel with'sodium hydroxideand'ex5 U hY l q af 7' y 4 traeted withmethylene ehloridegTheorganiolayeris I fl Pheny i dried overanhydrousealcium sulfate and stripped in i 3' 4t Y '-2(.l*i g g m q chlm'ldet vacuofft'o give .'6,7 diniethoxy l-(4ffluorophe nyl(- gal fl 8'8"" {33 .5?-

t i J l,2.3;4-tetrahydroisoquinoline.; After; crystallization .31.; Pt-1 h l' 'P =9yl l,2, .4- from a mixture of ethyl ether and n-hexane, that prodn f l' fi q fiq m 7 uct melts at about 0; soocrfl d hydro-2(iHHsoqurnolmeearbonylchloride. Substitution :iof 1f; 5 an equivalent quantity of 'm=h l -P y p-chlorobenzaldehyde for the?p-fluorobenzaldehyde 550 used above and substantial repetitionibfthe .ror'eg'pihga dc proeedureaffords l-v(4fc hloropheny )-6 ,7 d imethoxya 7 t 1 I ylenedioxy-i-phenyl-l.2,3.4- :1 63f:i'ffg mql f" -;719m? tetrahydroisoquinoline affords '6,7 -ethylenedioxy-l. q IAenylfBA-dihydro-HlH)-isoquinolirieearbonyl chlo- EXAMPLE-1- i r i I -EXAMPLE8' tetrahydroisoquinoline affords t5,7-methylenedioxyl phenyl-3.4:dihydro-Z( lll)-isoquinolinecarbonyl ehlm To a ev ,Ni va t7'idlmethoxy'tl'i ."x-TolO parts byvolumeof Z-diethylaminoethylamine y .3M y m s q in e and l akv j i is "added 3.0 parts of 6,7-dimethoxy l-phenyl-3,4- triethylamine'in 220 parts of benaene is added porti o n-. I se. atroom temperature over -s40 minuteperiod," Jagthermie reaction ensues The mixtureis heated overa P of a"bcnlenelolufioncomainlni 20 Pamflf steam bath for approximately 30 minutes. (Alterna- 'phosgene. After the addition is (BO mph". the reaction' fivly. 'h mixture can bgmaintalngd at room tempera.

mixture is stirred at room temperatureforariadditional 6 time overnight.) The'reaction' mixture is then poured 90minutes, then is heated up;.t o reflux forf3Q minute's and filtered. The filtrate is'evapo'rated to afford a'resid- "layer'is dried over anhydrouscalcium sulfate and evap-- intowatef'fand 'extraotedflwithethyl ClhCfuTl'W etherual solid, ethyl etheris added and themixturefis tilorated to dryness. The solid'thus obtained iserystallized from a mixture of ethyl ether and n-hexsne to afford N-(Z-diethylaminoethyl)6.7-dimethoxy-l -phenyl- 3,4-dihydro-2( lH)-isoquinolecarboxamide, melting at about 97-98C.

Substitution of an equivalent quantity of 2 -dii sopropylaminoethylamine for the Z-diethylaminoethylamine used above and substantial repetition of the foregoing procedure affords N-(2-diisopropylaminoethyl)- 6,7-dimethoxyl -phenyl-3 .4-dihydro-2( l H )-isoquinolinecarboxamide, melting at about l09-l C. That compound can be represented by the following structural formula:

2(lH)-isoquinolineearbonyl chloride and i0 parts by volume of 3-diethylaminopropylamine are cooled and then combined in the cold. The resultant mixture is allowed to stand at room temperature overnight. then is poured into water and extracted with ethyl ether. The ether extract is dried over anhydrous calcium sulfate. concentrated to a small volume underreduced pressure and cooled in ice to effect crystallization. There is thus obtained N-(3- -diethyla minopropyl)-6,7-dimetl1oxy-l-phenyl-3,4-

EXAMPLE 9 When an equivalent quantity of 2- piperidinoethylamine is substituted for the 2-diethylaminoethylamine used in Example 8 and the procedure described in the first paragraph of that example is substantially repeated. there is obtained. after crystalli zation from ethyl ether, 6,7-dimethoxy-l-phenyl-n-(N- isoquinolinecarboxamide'. That compound melts at about l0l-l02C. and can be represented by the following structural formula:

EXAMPLE l0 An equivalent quantity of'2-morpholinoethylaniine is 3 substituted for the] 2-diethylaminoethylaminef"em ployedzin-Example 8 and the'lproceduredescribed in dihydro2(lH)-isoquinoiinccarboxamide melting at about 92-93C.

Repetition of the above procedure using an equivalent quantity of Z-dimethylaminoethylamine affords 6,- 7-dimethoxy-N-(Z-dimethylaminoethyl)-l-phenyi-3,4- dihydro-2(lH)-isoquinoiinecarboxamide melting at about 60C.

in a similar manner, substitution of an equivalent a quantity of 3-dimethylaminopropylamine in the procethe first paragraph of that exampleis repeated After the mixture is'heated over a steam bath for 3Q'minutes,

: it is poured into 'water and extractedwithfmethylene chloride, The 'me'thylenelt-chloride extract is "then stripped of solvent in vacuo and the residue is crystal lized from a mixtureofniethylenechlorideand' ethyl ether. Thcp'roduct obtained in thisflmanner'is" 6 dimethoxy-N-(Z-morpholinoethyl) lphenyi-3,4-dihydro-2( l H )-is0quinoiinecarboxamide.

meltingat about l30-l3 lC.

EXAMPLE ll 3.0 Parts of dimethoxy-i-phenyl-Ii.4 dihydrodure detailed above affords 6,7-dimethoxy-N-(3- dimethylaminopropyl)- l -phenyl-3,4-dihydro-2( lH isoquinolinecarboxamide.

EXAMPLE i2 phenyl )-3.4-dihydro-2( iii )-isoquinolinecarboxamide as'a low melting solid. That compound is characterized by infrared absorption maxima in chloroform at about l.640"and 3;400 cm" Substitution of i an equivalent quantity of 2-[N-cyclohexyKmethyiamino)lethylamine for the Z-diisopropylaminoethylamine used above and substantial repetition of the foregoing procedure affords N-{2-[Neeyclohexyl)methylamino)]ethyl-6.7-} dimethoxy-l-(4-methoxyphenyl)-3,4-dihydro-2(1H)- isoqulnolinecarboxamid e. as a low melting solid. That compound exhibits infrared absorption maxima in chloroform at about 1.640 and 3.420 em and can be represented by the following structural formula EXAMPLE 13 4.0 Parts of 2-diisopropylaminoethylamine in 75 parts of chloroform is added portionwise, at room temperature, to a mixture of 8.0 parts of 6,7-dimethoxyl-(3,4-dimethoxyphenyl)-3,4-dihydro-2(1H)- isoquinolinecarbonyl -isoquinolinecarbonyl chloride and i parts of triethylamine in 225 parts of chloroform. After the addition is complete, the mixtureis stirred for 3 to 4 hours. allowed to stand overnight, and then washed with water. The chloroform layer is separated, dried over anhydrous calcium sulfate and concentrated under reduced pressureflhe solid material obtained in this manner is crystallized from ether to give N-(2-diisopropylaminoethyl)-6,7-dimethoxy-l- 3 ,4-dimethoxyphenyl)-3 ,4-dihydro-2(1H)- isoquinolinecarboxamide; melting at about ,1 i4-ll5C. 2 t

When an equivalent quantity of 2-[N-cyclohexyl(methylamino)]ethylamine is substituted for the 2-diiso-- EXAMPLE 14 When an equivalent quantityof l-phenyl-3,4-

dihydro-2( lH)-isoquinolinecarbonyl chloride is substituted for the 6,7-dimethoxy-i (3,4-dimethoxyphenyl)- 3,4-dihydro-2( 1H )-isoqulnolinecarbonyl chloride" used in Example l3 and the proceduredetailed inkthe first paragraph ofthat example is substantially repeated.

there is obtained, after crystallization from a mixture of diisopropylaminoethyD-l phenyl-3,4-dihydro-2("1); r

isoquinolinecarboxarnide, melting at-; ,--ab out l0 1 -l 03C. Thatcornpound can be representedby the structural formula; q

EXAMPLE i5 Equivalent quantities of 2-[N-cyclohexyl)me- EXAMPLE i 6 Equivalent .quantities of 2-[Ncyclohexyl(methylamino)]ethylamine and 6-benzyloxy-7-methoxy-lphenyl-3.4-dihydro-2( iH)-isoquinolinecarbonyi chloride are substituted for the 2-diisopropylaminoethylamine 2 and 6,7-dimethyoxyi (3,4-dimethoxyphenyl)-3,4-dihydro-2( l H isoquinolinecarbonyl chloride used in Example 13 and the procedure described therein is substantially repeatedg, affording tS-benzyioxy-N- 2-[N- cyclohexyKmethylamino)lethyl -7-meth'oxy-l-phenyl- 3 ,4-dihydro 2( lH )-isoquinolinecarboxamide. The

product mel'ts at l0 9- -l 10C,." 2],The procedure described in the: first paragraph of Examplel 3 is re peated, except; that an equivalent quantity of; 6 -benzyi oxy 1methoxy-. l -'phenyl-3 ,4-dihydro- 2(l H)-isoquinolinecarbonyl chloride is used in place of the 6,7-dimethoxyl 3,4-dimethoxyphenyi)-3 ,4- dihydro-2( lHhisoq'uinoliniecarbonyl chloride and the product iscrystallized from a mixture of methylene chloride and n-hexane.- Obtained in this manner is 6- beniyloxy-N-(2 diisopropylaminoethyl)- 7-methoxyi -phenyl-3.4-dihydro-2( ll-l isoquinolinecarboxamide. which melts at about i$ 0-1S2C.' and can be represented by the following structural formula:

l42-l44C. after crystalliaation from a miatt'tlre of 6,7-dirnethoxy-3.4-dihydro- 2(ll-l)- isoquinolinecarboxa after crystallization froma mixture of ethylether and EXAMPLE I? 7-Benzyloxy-N-( Z-diisopropylaminoethyl -6- methoxyl -phenyl-3 .4-dihydro l-2( 1H)- isoquinolinecarboxamide, j about melting at methylene chloride and n-hexane;

7-Benzyloxy-N--2 [N-w cyclohexyl(methylamino)]ethyl -6-methoxy-l phenyl- 3,4-dihydro-2( lH)-isoquinolinecarbo tamide, melting 3,4-dihydro -2( lH)-isoquinolinecarboxarnide; which 35 melts at about 87-89C. ane: crystallization from nhexane.

dihydro-2(1H)-isoquinolinccarboxamide, which melts at about l42-'l43C. after crystallization from a mixture of methylene chloride-and n-hexa ne.

l-(4-ChlorophenyD-N. (Z-diisopropylaminoethyliy vmelting at isoquinolinecarboxamide.

ethyl and n-hexane, I

isoquinolinecarboxamide. Qwhich melts 1",: at',.,

phenyl-3.4 -dihydro-'2( l-l l-isoqtiinollnecarboitamide;

n-hexane.

- abe p-il28,-l29C. aftercrystallization"froma mixturel'of r v C jj ammoethyl),-15(4-methoxyphenyl) Idihydro-2( lH)-isoquinolinecarboxamide.

l-Benzyl-6,7-dlmethoxy-N-( 2- hexamethyleneiminoethyl)-3.4-dihydro-2( l H isoquinolinecarboxamide.'

6.7-Dimethoxy-N-l 2-( 4-methyll piperazinyl- )ethy- 'l-phenyl-3.4-dihydro-2( l H )-isoquinolinecurboxamidc.

6.7-Dirnethoxyl -phenyl-N-[ 2-( 4- phenylpiperidino)ethyl 1-3 .4dihydro-2( l H isoquinolinecarb'oxamide.

6.7-Dimethoxy -l-phenyl- N-l2-(l-pyrrolidinyllclthyl]-3 ,4-dihydro- 2( lH)-isoquinolinecarboxamide.

N-(Z-Diisdpropylaminoethyl)-7-methyl-l-phenyl- 3,4 -dihydro-2(1H)-isoquinolinecarboxamide.

-N-(Z-Diisopropylaminoethyl) 6,7 methylenedioxyl phenyl-3, 4-dihydro-2( l H )-isoquinolinecarboxamide. N(Z-Diisopropylaminoethyl)-6,7-ethylenedioxy-l- N 2-[N-Cyclohexyl(methylamino)lethyl -6,7- methylehedioxyv I l-phenyl-3,4-dihydro-2( l H )-isoquinolinecarboxamide.

N- 2-[N-Cyclohexyl(methylarnino)lethyl -6,7- ethylenedioxy-l-phenyl-3,4-dihydro-2( l H i soquinolinecarboxamide.

EXAMPLE l8 -Subsitution of anequivale nt'quantity of N,N.N'-

' trimethylethylenediamine for the Z-diisopropylaminoe- ""thylamine-used in Example 12 and substantial repetition ofjthe procedure detailed in the first paragraph of thatexample affords 6,7 -dimeth oxy-N-(2-dimethyl- -N-methyl-3 ,4-

ln a'similar manner. used of equivalent quantities of 6,7-dimethoi ty -i phenyl-3',4- dih ydro-2(l H)-isoquin olinecarbonyl chloride inipla ceof the dialk'ylaminoalkylv amine and isoquinolinecarbonyl chloride employed in Eaarrlple l2 affords N-(Z- diisoprop ylamihoethyl)Q6fI-tlimethoaty-N isopropyll EXAMPLE l9 solution of 2.0 parts of 2-chloroethylisocyanate in approximately 14 parts of methylene chloride is added portionwise, at room temperature, to 5.0 parts of 6,7-

is stirred for 2 hours. then is stripped of solvent under reduced pressure. The residue is triturated with ether to give. as a solid. N-(2-chloroethyl)-6.7-dimethoxy-lphenyl-3 .4-dihydro-2( lH )-isoquinolinecarboxamide.

EXAMPLE A mixture of 3.0 parts of the N-(2-chloroethyl)- 6 ,7-dimethoxyl -phenyl-3.4-dihydro-2( l H)- isoquinolinecarboxamide prepared in Example l9 and 4.3 parts of piperidine in approximately 40 parts of 2 -butanonc is heated at 65C. for 20 hours. The reaction mixture is then stripped in vacuo and the residue is taken up in dilute aqueous potassium bicarbonate solution and methylene chloride. The organic layer is dried and stripped in vacuo and the, residue is crystallized from ether to afford 6,7-dimethoxy- I v l-phenyl N-(Z-piperidinoethyl )-3.4-dihydro-2( "1 isoquinoiinecarboxamide. melting at about 10ll02C.

Substitution of an equivalent quatity of 4- benzylpiperidine for the piperidine used above and substantial repetition of the foregoing procedure affords N-i 2-(4-benzylpiperidino)ethyl]-6.7-dimethoxy-lv phenyl-3,4-dihydro-2-( lH)-isoquinolinecarboxamide.

in a similar manner. use of l-phenylpiperazine in place of the piperidine employed in the procedure detailed in the first paragraphof this example gives 6,7-dimethoxy-l-phenylfN-[2-(4 phenyl-l-piperazinyl)ethyl]3 .4-dihydro- 2(l H)-isoquinolinecarboxamide.

EXAMPLE 2i 2.0 Parts of '6-benzyloxy-N- (Z-diisopropylaminoethyi) 7-methoxy- I -phenyl-3.4-dihydro-2( lH isoquinolinecarboxamide is dissolved in approximately 80 parts of,methanol. 0.2 Part of a 5% palladium-on-v carbon catalyst is'addeda nd the mixture is shaken at room temperature and a pressure of about2 psi for approximately 23hours or until one molecular equivalent of hydrogenhas been absorbed. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to give 'an'oil which solidifies upon trituration with n-pentane. .Thatsolid is crystallized from a mixture of methylene chloride-and nhexane to afford ;1N (2-diisopropylaminoethyl)-6 isoquinoiinecarboxamide., melting at about.9 l-.92 C.'

The procedure I'de'scribed above is repeated 'usingj65 benzyloxy-N- 2-[ N-cyclohexyl(methylamino)lethyl tion isoquinoiinecarboxamide. That compound is obtained as an amorphous solid and is characterized by infrared absorption maxima in chloroform at about L635. 3,400 and 3.560 cml.

EXAMPLE 22 2.0 Parts of N-(Z-diisopropylaminoethyl)-l-phenyl- 3.4-dihydro'2(lH)-isoquinolinecarboxamide is dissolved in 22.8 parts of methyl iodide and placed in a steam oven at 65C. for about l6 hours. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in ethanol. Ethyl ether is added and the mixture isrefrigerated until crystallizaoccurs. The product. which is N-(2- diisopropylaminoethyl)-l-phenyl-3,4-dihydro- 2( l H)-isoquinolinecarboxamide 'methiodide. is separated and recrystallized from a mixture of ethanol and ethyl ether.

EXAMPLE 23 pressure to give N-(2-diisopropylaminoethyl)-6,7

dimethoxy- N-methyll -phenyl-3'.4-dihydro-2( l H isoquinoiinecarboxamide.

What is claimed is:

l. A compound of the formula i o 7 I it -C-t|l-A1lt-IR R R (CHQ)B V wherein X and X are each selected from the group single methylenedioxy or ethylenedioxy group; Y and Y" are each selected from the group consisting of hy- *drogen. halogen and lower'alkoxytn'is selected from exhibits infrared absorption maxima in chloroform at the group consisting 'of 0 and l; R is selected from the group consisting of. hydrogen and lower alkyl. Alk is lower alkylene of 2 to 6 carbon atoms separating the nitrogen atoms attached thereto by at least 2 carbon atoms; and NRR" is selected from the group consisting of di(lower alkyl) amino, N-cyclohexylflower alkylamino), l pyrrolidinyl.hexamethyleneimino. piperidino, 4-phenylpip'eridino, and .4-benzylpiperidino 2. A compound according to claim 1 which has the formula 7. A compound according to claim 1 which is N-(2- diethylaminoethyl)-6.7-dimethoxy-l-phcnyl-3.4- dihydro-2( l H )-isoquinolinecarboxamide.

g 8. A compound according to claim I which is N-(Z- x II lower alkyl 5 diisopropylaminoethyl)-6 ,7-dimethoxy-l-phenyl-Zl.4- xl lI-C-I-Alk-I dihydro-2( lH)-is0quinolinecarboxamide.

l W 9. A compound according to claim I which has the formula K) x I x -Cm-.CK CH 'N yr wherein X and X are each selected from the group consisting of hydrogen, lower alltoxy. hydroxy. benzyloxy and .methyl, or X and X' together represent a single methylenedioxy or ethylenedioxy group; Y and Y' are each selected from the group consisting of hydrogen, halogen and lower alkoxy; n is selected from the group consisting of 0 and l; R is selected from the group consisting of hydrogen and lower alkyl; and All:

ll -c-la-nx-I- where in Alk is lower alkylene separating the nitrogen atoms attached thereto by at least 2 carbon atoms.

wherein X and X' are each selected from the group consisting of lower alkoxy. hydroxy and benzyloxy, or X and X together represent a single methylenedioxy or ethylenedioxy group; and Y and Y' are each selected from the group consisting of hydrogen. halogen and lower alkoxy.

10. A compound according to claim 1 which is N-{Z- [N-cyclohexyl(methylamino)]cthyl}-6,7-dimethoxy-l- (4-methoxyphenyl)-3 .4-dihydro-2-(1H)- isoquinolinecarboxamide.

11. A compound according to claim 1 which is N-{2- IN-cyclohexyl)methylamino) lethyl }-6,7-dimethoxyl phenyl-3,4-dihydro-2( 1H )-isoquinolinecarboxamide.

12. A compound according to claim 1 which is 7- eniyloxy-N-{2-l N-cyclohexyl( methylamino) lethyl} loior alkyl -methoxyl -phenyl-3.4-dihydro-2( 1H)- isoquinolinecarbo'xamide.

# l i i i Page 1 of 2 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 9 PATENT NO. 3,905,982

DATED September 16, 1975 INVLNTOWS) Peter K. Yonan It is certified that error appears in the above-identified patent and that said Letters Patent Q are hereby corrected as shown below:

Column 2, line 9, "heat" should read heart Column t, line 26, "temperature 60" should read temperature to 60 a Column 5, line tO, after "or" delete "ethylenedioXy-g" and insert 3A Column 7, line 21, "tetrahydroisoquinoine" should read tetrahydroisoquinoline a Column 9, line 65, "dimethoxy" should read 6,7-dimethoxy Column 10, line 61, "ethyl-6,7}" should read ethyl}6,7

Column 11, line 22, delete first "isoquinolineoarbonyl" Column 11, line 30, "-1-" should read -l-( Column 11, line 38, after first "N" insert and after "ethyl" insert a Column 12, line 12, after first "N-" insert Column 12, line 13, after "ethyl" insert Column 12, line 52, after "-N" insert I Column 12, line 53, after "ethyl" insert UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION it 33 cemfled that em: appears are hereby (Inflected as shown below "1%" insert Column l3,

13, line after "ethyl" insert line l-S Ii Column ;-I-" insert I Column ine Column line after "16-" insert L Column olumr; l i, line l9, ")ethy should read )ethyllline 32, after after Column l lo,

after "ethyl insert Column l l, line 35, first "16-" after "ethyl" insert Column 1'4, line 50, "used" should read use Column 15, line 51, after after "ethyl" Column 15, line 5 T, after Column 15, line 55, after first insert first first "N" insert insert "N" insert Page 2 of 2 m the above-Tdents ed patent and that saw Letters Patent "ethyl" insert ethyl" insert and and

and

and

"ethyl" insert Column 18, line 36, after "ethyl}" insert Signed and Scaled this [SEAL] eleventh of May 1976 A lies I."

RUTH C. MASON Allvsrmg ()j/iu'r C. MARSHALL DANN ummisxiuncr nj'lun'nrs ami Trademarks 

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 which has the formula
 3. A compound according to claim 1 which is N-(2-diisopropylaminoethyl)-1-phenyl-3,4-dihydro-2(1H) -isoquinolinecarboxamide.
 4. A compound according to claim 1 which is 6-benzyloxy-N-(2-diisopropylaminoethyl)-7-methoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide.
 5. A compound according to claim 1 which is 7-benzyloxy-N-(2-diisopropylaminoethyl)-6-methoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide.
 6. A compound according to claim 1 which has the formula
 7. A compound according to claim 1 which is N-(2-diethylaminoethyl)-6,7-dimethoxy-1-phenyl-3,4-dihydro-2(1H) -isoquinolinecarboxamide.
 8. A compound according to claim 1 which is N-(2-diisopropylaminoethyl)-6,7-dimethoxy-1-phenyl-3,4-dihydro-2(1H) -isoquinolinecarboxamide.
 9. A compound according to claim 1 which has the formula
 10. A compound according to claim 1 which is N-(2-(N-cyclohexyl(methylamino))ethyl)-6,7-dimethoxy-1-(4methoxyphenyl)-3,4 -dihydro-2-(1H)-isoquinolinecarboxamide.
 11. A compound according to claim 1 which is N-(2-(N-cyclohexyl)methylamino))ethyl)-6,7-dimethoxy-1-phenyl-3,4-dihydro -2(1H)-isoquinolinecarboxamide.
 12. A compound according to claim 1 which is 7-benzyloxy-N-(2-(N-cyclohexyl(methylamino))ethyl)-6-methoxy-1-phenyl-3,4 -dihydro-2(1H)-isoquinolinecarboxamide. 